Wild-type cyclin E and hyperactive low-molecular-weight (LMW) isoforms accumulate in human breast tumors and are associated with poor disease outcome. We hypothesized that a pro-inflammatory tumor environment induces cyclin E and used immunohistochemistry to study cyclin E expression in relation to tumor monocyte density and the expression of cyclooxygenase-2 (COX2) and nitric oxide synthase-2 (NOS2) in 243 breast tumors. Cyclin E overexpression correlated with the expression of LMW cyclin E isoforms and breast cancer survival. Cyclin E expression was positively associated with the number of CD68-positive tumor monocytes and the expression of COX2 and NOS2. Cyclin E expression also correlated with the estrogen receptor (ER) and p53 status, microvessel density (MVD) and Akt phosphorylation at Ser473. Multivariate logistic regression showed that the relationship between cyclin E and the ER status (Odds ratio (OR), 9.7; 95% confidence interval (CI), 4.2-22.2), p53 status (OR, 4.6; 95% CI, 2.1-9.9), MVD (OR, 2.7; 95% CI, 1.1-6.7), and COX2 expression (OR, 2.3; 95% CI, 1.1-5.0), is independent from other factors. Our results indicate that the nuclear accumulation of cyclin E is more prevalent in breast tumors with a pro-inflammatory environment defined by a high monocyte count and the expression of COX2 and NOS2. Because cyclin E overexpression, tumor monocyte infiltration and the absence of ER expression are interrelated in breast cancer, possibly through a common pathway, targeting both cyclin E overexpression and tissue inflammation could be a new approach to treat ER-negative tumors.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]